Research in the Cellular Neurology Unit focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, dystonia, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for many of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. [unreadable] [unreadable] In this project, we are emphasizing investigations into the regulation of mitochondrial morphology within cells. Indeed, fusion and fission events that regulate mitochondrial morphology are essential for proper mitochondrial function, and their regulation is increasingly recognized in diverse cellular functions. Mitochondrial fission events in mammals are orchestrated by at least two proteins; the dynamin-related protein Drp1 and the integral membrane protein Fis1. The reciprocal process of mitochondrial fusion also requires large GTPases of the dynamin superfamily: OPA1 and the mitofusins Mfn1 and Mfn2. Since mutations in Drp1, Mfn2, and OPA1 have been identified in patients with inherited neurological disorders, and there is prominent fragmentation of mitochondria during programmed cell death, insights into the regulation of these processes is highly relevant clinically.[unreadable] [unreadable] We have recently published a study demonstrating that cAMP-dependent protein phosphorylation of the Drp1 protein regulates its GTPase activity as well as mitochondrial morphology. In addition, we have identified the sites of sumoylation on the Drp1 protein, and are currently using dominant-negative approaches to determine the functional role of sumoylation in Drp1 function. Lastly, we have recently completed a study of the Drp1 A395D mutation that caused a neonatally fatal mitochondrial disorder due to markedly diminished mitochondrial fission. Using yeast two-hybrid tests, we were able to show that this mutation resulted in loss of inter- and intramolecular interactions of the Drp1 protein, resulting in a defect in proper higher-order assembly. In ongoing studies, we have identified a number of Drp1-interacting proteins that we are currently evaluating. [unreadable] [unreadable] Though most of our efforts are focused on the regulation of mitochondrial fission, we have several collaborative projects related to the regulation of mitochondrial fusion. These are particularly focused on the proteolytic processing of the OPA1 protein.[unreadable] [unreadable] Together, these studies are continuing to provide critical insights into the regulation of mitochondrial morphology within a cell, an area of increasing clinical relevance and importance.